MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

Ekin Ucuncu, Karthyayani Rajamani, Miranda S. C. Wilson, Daniel Medina-Cano, Nami Altin, Pierre David, Giulia Barcia, Nathalie Lefort, Céline Banal, Marie-Thérèse Vasilache-Dangles, Gaële Pitelet, Elsa Lorino, Nathalie Rabasse, Eric Bieth, Maha S. Zaki, Meral Topcu, Fatma Mujgan Sonmez, Damir Musaev, Valentina Stanley, Christine Bole-Feysot, Patrick Nitschké, Arnold Munnich, Nadia Bahi-Buisson, Catherine Fossoud, Fabienne Giuliano, Laurence Colleaux, Lydie Burglen, Joseph G. Gleeson, Nathalie Boddaert, Adolfo Saiardi () and Vincent Cantagrel ()
Additional contact information
Ekin Ucuncu: Université de Paris, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163
Karthyayani Rajamani: Université de Paris, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163
Miranda S. C. Wilson: University College London
Daniel Medina-Cano: Université de Paris, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163
Nami Altin: Université de Paris, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163
Pierre David: Transgenesis Platform, Laboratoire d’Expérimentation Animale et Transgenèse (LEAT), Imagine Institute, Structure Fédérative de Recherche Necker INSERM US24/CNRS UMS3633
Giulia Barcia: Université de Paris, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163
Nathalie Lefort: Université de Paris, iPSC Core Facility, Imagine Institute, INSERM UMR 1163
Céline Banal: Université de Paris, iPSC Core Facility, Imagine Institute, INSERM UMR 1163
Marie-Thérèse Vasilache-Dangles: AP-HP, Hôpital Necker-Enfants Malades
Gaële Pitelet: Service de Neuropédiatrie, CHU Nice
Elsa Lorino: ESEAN, 44200 Nantes, Service de maladies chroniques de l’enfant, CHU Nantes
Nathalie Rabasse: Service de pédiatrie, hôpital d’Antibes-Juan-les-Pins
Eric Bieth: Service de Génétique Médicale, CHU Toulouse
Maha S. Zaki: National Research Centre
Meral Topcu: Hacettepe University
Fatma Mujgan Sonmez: Guven Hospital, Child Neurology Department
Damir Musaev: University of California San Diego
Valentina Stanley: University of California San Diego
Christine Bole-Feysot: Université de Paris, Genomics Platform, Imagine Institute, INSERM UMR 1163
Patrick Nitschké: Université de Paris, Bioinformatics Core Facility, Imagine Institute, INSERM UMR 1163
Arnold Munnich: Université de Paris, Translational Genetics Laboratory, Imagine Institute, INSERM UMR 1163
Nadia Bahi-Buisson: Université de Paris, Genetics and Development of the Cerebral Cortex Laboratory, Imagine Institute, INSERM UMR 1163
Catherine Fossoud: Centre de Référence des Troubles des Apprentissages, Hôpitaux Pédiatriques de Nice CHU-Lenval
Fabienne Giuliano: Service de Génétique Médicale, Centre Hospitalier Universitaire de Nice
Laurence Colleaux: Université de Paris, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163
Lydie Burglen: Université de Paris, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163
Joseph G. Gleeson: University of California San Diego
Nathalie Boddaert: INSERM UMR 1163 and INSERM U1000, AP-HP, Hôpital Necker-Enfants Malades
Adolfo Saiardi: University College London
Vincent Cantagrel: Université de Paris, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Inositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol-polyphosphate phosphatase 1 gene (MINPP1). Patients are found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We find that patient-derived and genome edited MINPP1−/− induced stem cells exhibit an inefficient neuronal differentiation combined with an increased cell death. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-19919-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19919-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-19919-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().